Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the formation of plaques and neurofibrillary tangles in the brain. While the mechanisms of the cause and progression of the disease are poorly understood, over time it results in loss of cognitive abilities and neuronal loss in several regions of the brain. The plaques are believed to be formed from deposits of amyloid beta (Aβ) peptide and are widely believed to be linked to such disease symptoms, though the causative contribution of such plaques to the disease is not well-understood.
Aβ peptides are formed from the amyloid precursor protein (APP) by proteolytic processing. This processing is effected by the cooperative activity of several proteases, namely α-, β- and γ-secretase, which results in a number of fragments of differing length. The fragments found in the plaques include mostly those having a length of 40 or 42 amino acids (Aβ40, Aβ42—defined below). These proteins tend to polymerize in an aqueous environment. Thus, they may be present in a variety of different molecular forms (e.g. monomers, dimers, oligomers, etc.). A simple correlation of the deposition of insoluble protein with the occurrence or progression of dementia disorders such as, for example, Alzheimer's disease, has proved to be unconvincing (Terry et al., Ann. Neurol. 30: 572-580, 1991; Dickson et al., Neurobiol. Aging 16: 285-298, 1995). In contrast, the loss of synapses and cognitive perception seems to correlate better with soluble forms of Aβ(1-42) (Lue et al., Am. J. Pathol. 155: 853-862, 1999; McLean et al., Ann. Neurol. 46: 860-866, 1999).
There exists a tremendous, unmet therapeutic need for the development of biologics useful in the study, diagnosis, prognosis, and/or treatment in Alzheimer's disease. In particular, there is a need for the development of biologics that bind the soluble form of the Aβ fragments, particularly Aβ40 and Aβ42. Such a need is particularly evident in view of the lack of understanding of this disease after decades of research. Such Aβ binding proteins will allow for the elucidation of the biological properties of the proteins and other biological factors responsible for this debilitating disease. The need is also evident from increasing longevity of the general population and, with this increase, an associated rise in the number of patients annually diagnosed with Alzheimer's disease or related disorders. Aβ binding proteins will allow for proper diagnosis and/or prognosis of Alzheimer's disease in a patient experiencing symptoms thereof, a diagnosis which can only be confirmed upon autopsy at the present time. Ideally, such biologics may also be used in the prevention and/or treatment of such a disease.